Cardiovascular Toxicity in Cancer Survivors: Current Guidelines and Future Directions

Introduction

An individual is defined by the National Cancer Institute as a survivor "from the time of diagnosis through the balance of his or her life."1 Due to improved diagnosis and treatment, the number of cancer survivors in the United States reached nearly 15.5 million currently.2,3 More than 60% and 40% of cancer survivors are alive 5 and ≥10 years after diagnosis, respectively, contributing to a growing population of aging survivors at risk for late or long-term treatment-related effects and comorbidities.4,5 Analysis of the SEER (Surveillance, Epidemiology, and End Results) database demonstrated that approximately 46% of survivors were age 70 or older in 2012.5 Breast, prostate, and colorectal cancer and melanoma accounted for approximately 58% of survivors.5

With longer survival, emphasizing overall health through management of late and long-term treatment effects and promotion of healthy lifestyle behaviors is increasingly important. Cardiovascular issues such as cardiomyopathy, arterial disease, hypertension, and vascular and metabolic issues can manifest during or after therapy due to treatment-related toxicities. Compared with the general population, adult survivors of multiple myeloma, lung cancer, non-Hodgkin lymphoma, and breast cancer have a higher risk of cardiovascular disease (CVD).6 Similar trends are seen in childhood and young adult cancer survivors, largely attributable to exposure to cardiotoxic therapies as well as the development of cardiovascular risk factors later in life.7,8 Cardiovascular toxicities from chemotherapy, radiation, and targeted or hormonal treatments can interfere with optimal cancer management, decrease quality of life, and affect overall survival. Cardiovascular comorbidities and toxicities now represent a leading cause of morbidity and mortality in cancer survivors9-11 and the leading cause of death in breast and colorectal cancer survivors approximately 10 years after cancer diagnosis.12,13

Given improving cancer-specific survival and the growing burden of CVD in the survivor population, attention to cardiovascular reserve has become increasingly important. Cardiovascular reserve may be affected by multiple treatment and patient factors. Chemotherapy can cause pulmonary dysfunction, anemia, skeletal muscle and cardiomyocyte dysfunction, endothelial dysfunction, and arterial stiffness. Patient factors including presence of comorbidities and lifestyle factors, such as physical inactivity, excess body weight, and tobacco use, also impact cardiovascular reserve.14 Recognizing the intersection between CVD and cancer, Hershman et al. recently evaluated the impact of cardiovascular risk factors on cardiac events and survival in patients with breast cancer enrolled in Southwest Oncology Group (SWOG) clinical trials, concluding that increasing risk factor burden was associated with higher rates of all-cause mortality and marginally lower rates of progression-free and cancer-specific survival.15

Given the changing landscape of both cancer and cardiovascular comorbidity, multiple professional organizations have developed guidelines to address cardiovascular issues in cancer survivors. Most available guidelines focus on treatment-induced cardiac dysfunction and heart failure (HF), primarily associated with anthracycline toxicity because this is the most commonly recognized treatment-related cardiovascular issue. In this review, we will evaluate the current guidelines that address management of treatment-related cardiotoxicity in cancer survivors, highlighting similarities and differences, and discuss barriers and future directions in this emerging field of interest.

Cardiotoxicity Guidelines: The Current Landscape

Over the course of the past decade, multiple organizations have identified cardiovascular toxicity as a clinically relevant issue in cancer survivors and began to formulate recommendations and guidelines to address this problem. The guidelines primarily concentrate on anthracycline-based cardiac toxicity, but their recommendations can be extrapolated to agents directed at HER2 such as trastuzumab, pertuzumab, lapatinib, and trastuzumab emtansine. Each guideline focuses on a different population, resulting in slight variations in recommendations across similar but not identical populations defined within the broader definition of cancer survivor.

The International Society of Geriatric Oncology (SIOG) focuses on elderly patients who are being considered for anthracycline-based therapy, recommending that age alone should not limit the use of anthracyclines.16 Its guideline advocates rigorous screening to exclude high-risk patients, recommending clinicians take into account prior anthracycline exposure and cardiovascular comorbidity (hypertension, diabetes, and coronary artery disease). For patients receiving anthracyclines, recommended ways to reduce cardiotoxicity risk include use of continuous infusion and/or liposomal anthracycline formulations, preferred use of epirubicin when clinically appropriate, use of concurrent dexrazoxane, sequential administration of anthracycline and trastuzumab, and aggressive management of cardiovascular risk factors through lifestyle modifications and use of appropriate medical therapy like lipid-lowering agents and blood pressure management with angiotensin-converting enzyme (ACE) inhibitors and/or beta-blockers. In addition, the SIOG recommends regular monitoring of cardiac function in patients age ≥70 through measurement of left ventricular ejection function (LVEF) via the same method every 2-3 cycles, with special attention to declines >10% and early management of cardiac dysfunction, including consideration of treatment discontinuation as clinically appropriate if LVEF declines below the lower limit of normal, even if asymptomatic. Moreover, the SIOG urges physician to keep in mind the potential for cardiovascular events during long-term follow-up for patients who have been exposed to anthracyclines.

The European Society for Medical Oncology (ESMO) published clinical practice guidelines to address treatment-induced cardiovascular toxicity regardless of age.17 Unlike other guidelines, the ESMO guidelines encompass left ventricular dysfunction, myocardial ischemia, hypertension, and QTc prolongation and provide recommendations in four major areas: cardiovascular risk assessment and prevention, screening and monitoring of cardiac function during cancer treatment, management of pre-existing cardiac disease, and management of chemotherapy-induced, targeted agent-induced, or radiation-induced cardiotoxicity. ESMO recommends that all patients receiving cardiotoxic therapy undergo clinical cardiovascular assessment and robust management of risk factors and comorbidities before and during therapy. The guidelines identify doses of various anthracyclines associated with an increased cardiotoxicity risk and recommend assessment by echocardiogram, although multigated acquisition scan (MUGA) and magnetic resonance imaging are acceptable. For patients receiving anthracyclines and/or trastuzumab in the adjuvant setting, serial monitoring of cardiac function should occur at baseline; 3, 6, and 9 months during treatment; and at 12 and 18 months after initiation of therapy. For patients with metastatic disease, the panel recommends monitoring at baseline and then infrequently in the absence of symptoms. For patients who receive a cumulative dose of doxorubicin >240 mg/m2 or epirubicin >360 mg/m2, the guideline recommends assessment of cardiac function 4 and 10 years after anthracycline therapy. In addition to LVEF evaluation, they suggest performing baseline assessments of biomarkers (troponin I and B-type natriuretic peptide [BNP]) and periodic measurements during therapy (every cycle) to potentially identify patients who require further cardiac assessment or who are at risk for cardiotoxicity, despite limited data on the effectiveness of this strategy. Like the SIOG guideline, ESMO recommends that patients who develop left ventricular dysfunction should be managed according to HF standards and that all patients should be counseled on strategies to mitigate cardiovascular risk.

A 2014 joint expert consensus statement from the American Society of Echocardiography (ASE) and the European Association of Cardiovascular Imaging (EACVI) focused primarily on pretreatment and on-treatment cardiac risk assessment, advocating for early cardiology assessment in patients with low-normal ejection fraction prior to planned cardiotoxic therapy and annual cardiovascular-focused assessment of adult survivors after the completion of cardiotoxic therapy.18 Importantly, because many different definitions of cancer therapeutics-related cardiac dysfunction have been used historically, the committee specifically defined cardiotoxicity or cancer therapeutics-related cardiac dysfunction as a decrease in LVEF >10 percentage points to a value <53%, which is the normal reference value for two-dimensional echocardiogram. This expert consensus also acknowledged the use of global longitudinal strain as a potential marker for early detection of cardiotoxicity during cancer therapy. A reduction of >15% in global longitudinal strain from baseline immediately after or during anthracycline therapy may be predictive of cardiotoxicity; a reduction <8% may not be clinically significant. The use of cardiac imaging was left to clinician discretion, but echocardiogram was recommended as the preferred imaging modality when performed. The panel also suggested the use of serum biomarker evaluation, including troponin and BNP, but did not mandate testing due to a lack of well-defined predictive or prognostic benefits.

In 2015, the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines on Survivorship introduced an anthracycline-induced cardiotoxicity algorithm for disease-free survivors who have completed primary treatment for their cancers. This effort integrated cardiology and oncology perspectives on evolving scientific knowledge to establish recommendations, recognizing that HF is a progressive disorder and focusing on early detection and management. Based on the American College of Cardiology Foundation and American Heart Association stages of HF, asymptomatic anthracycline-treated patients were recognized to have stage A HF due anthracycline exposure despite no structural cardiac dysfunction. In this population, of which the majority of survivors is part, the guidelines emphasize management of underlying comorbidities and health behaviors to optimize risk reduction, with recommendations for cardiology referral for those with or suspected to have more advanced (stages B, C, or D) disease.

Recognizing the lack of high-quality data to inform benefits of routinely screening anthracycline-exposed survivors, the panel recommends a thorough clinical assessment for HF; survivors with ≥1 risk factor(s) in addition to anthracycline exposure could be considered for structural cardiac assessment with appropriate imaging within 12 months of the last anthracycline dose. Associated risk factors include chest radiation, combination therapy with known cardiotoxic agents (HER2 inhibitors with anthracyclines), age ≥65 years, exposure to high cumulative anthracycline dose (doxorubicin dose ≥300 mg/m2 or equivalent), known underlying CVD or risk-associated comorbidities including obesity, and low-normal (50-54%) baseline LVEF.19-21 The panel recommends two-dimensional echocardiogram coupled with Doppler flow studies as the imaging modality of choice but did not recommend concomitant use of strain or biomarker evaluation due to lack of strong data. The guideline also focuses on CVD prevention through healthy habits and is complimented by a separate algorithm on Healthy Lifestyles with recommendations for physical activity, weight management, and nutrition.

The American Society of Clinical Oncology (ASCO) recently published recommendations on the prevention and monitoring of systolic cardiac dysfunction in adult cancer survivors.22 This practice guideline addresses five issues: risk stratification, preventive strategies prior to initiation of cancer-directed therapy, preventive strategies during treatment, surveillance and monitoring approaches during therapy, and surveillance post-treatment. Specific risk factors for developing cardiac dysfunction include regimens involving high-dose anthracycline (doxorubicin ≥250 mg/m2) or high-dose radiation therapy (≥30 Gy); combination of anthracycline and radiation; use of lower-dose anthracycline (doxorubicin <250 mg/m2 or epirubicin <600 mg/m2) or trastuzumab in patients with multiple cardiovascular risk factors (smoking, hypertension, diabetes, dyslipidemia, and obesity), age ≥60 years, or baseline compromised cardiac function (LVEF 50-55%, history of myocardial infarction, and at least moderate valvular heart disease); and use of lower-dose anthracyclines followed by trastuzumab (sequential therapy). No recommendations are made on the risk of cardiac dysfunction in patients with exposure to kinase inhibitors or lower-dose anthracyclines or trastuzumab alone without additional risk factors. Recommended pre-treatment preventive strategies include screening for the above-mentioned risk factors and obtaining an echocardiogram prior to initiation of potentially cardiotoxic therapies. Like other guidelines, the ASCO panel also recommends managing modifiable risk factors throughout the treatment trajectory and incorporating strategies to prevent cardiotoxicity in patients receiving high-dose anthracyclines (use of dexrazoxane, continuous infusion, or liposomal formulation) as clinically appropriate.

To address monitoring during treatment, the panel recommends clinical evaluation for cardiac dysfunction and the use of echocardiogram and serum cardiac biomarkers, with referral to a cardiologist based on clinical findings. Routine surveillance with echocardiogram may be considered on-treatment for asymptomatic patients who are at increased risk and may be performed 6-12 months after cancer therapy completion in asymptomatic high-risk patients, with cardiology referral based on findings. If there is evidence of cardiac dysfunction, the decision to continue or discontinue cancer therapy should be made by the oncologist in close collaboration with a cardiologist after fully evaluating the circumstances and considering the risks and benefits of continued therapy.

Despite all focusing on treatment-related cardiotoxicity, each of the guidelines discussed above has a slightly different focus and audience (Table 1). Thus, although each recommends cardiac evaluation and surveillance, some guidelines focus on pre- and on-treatment care, and others address post-treatment surveillance. All guidelines agree that cardiac monitoring with imaging is appropriate, with the preferred use of echocardiogram common among all guidelines. In addition, there is general agreement on optimizing comorbid risk factors, with most guidelines emphasizing healthy behaviors. However, newer imaging technologies and the use of serum biomarkers are not uniformly recommended, reflecting the lack of strong data supporting their use and thus lack of consensus on applicability in this setting.

Table 1: Comparison of Guidelines on Cardiac Dysfunction in Cancer Survivors

Recommendations

SIOG

ESMO

ASE/EACVI

NCCN

ASCO

Identifying risk factors pre-treatment

Yes

Yes

Yes

Yes

Yes

Preventative strategies to minimize risk during therapy

Yes

Yes

No

No

Yes

Monitor for cardiotoxicity using LVEF

Yes

Yes

Yes

Yes

Yes

Use of cardiac biomarkers (troponin I, BNP)

No

Yes

Yes (troponin)

No

No

Cardiac imaging of choice for cardiac monitoring

Echocardiography or MUGA scan

Echocardiography

Echocardiography

Echocardiography

Echocardiography

Timing of cardiac monitoring in asymptomatic patients

Every 2-3 cycles of anthracycline exposure

Adjuvant anthracycline and/or trastuzumab: every 3 months during therapy, then 12 and 18 months after initiation of therapy

Agents associated with type 1 toxicity: completion of therapy, then 6 months after for doses <240 mg/m2 or equivalent.
Trastuzumab: every 3 months

Consider in high-risk patients within 1 year of the last anthracycline dose

Consider in high-risk patients 6-12 months after completion of therapy

Use of beta-blockers or ACE inhibitors

Yes

Yes

No

No

No

Evaluation and management of cardiovascular risk factors

Yes

Yes

No

Yes

Yes

Referral to cardiologist or cardio-oncologist

Yes

Yes

Yes

Yes

Yes

There are multiple barriers to developing evidence-based guidelines for cardiotoxicity management. There is no consistent definition of cardiotoxicity among trials and among adverse event classification systems. In addition, many studies of potentially cardiotoxic therapies exclude patients with underlying CVD or risk factors, thus making it challenging to extrapolate the actual rate of cardiac risk to the real-world cancer population. Long-term follow-up of trials utilizing cardiotoxic regimens is sparse, potentially skewing the picture to underestimate late events and longer-term morbidity. Small, typically single-institution studies evaluating surveillance strategies and therapeutic approaches for cardiotoxicity have not been consistent in their findings, although large randomized studies are underway to address some of these issues, including the SWOG S1501 phase 3 study investigating the use of carvedilol in preventing cardiotoxicity in patients with metastatic HER2-positive breast cancer and the SUCCOUR (Strain Surveillance During Chemotherapy for Improving Cardiovascular Outcomes) study, which is evaluating the role of strain in identifying subclinical left ventricular dysfunction in patients receiving cardiotoxic chemotherapy to guide cardioprotective therapy. Finally, there has not been a concerted effort in the oncology community to focus on cardiotoxicity because this might limit the use of effective cancer therapy, and extrapolation of data from non-cancer patient populations may not be optimal.23

Future Directions

Although current guidelines are a much-needed initial step in addressing cardiotoxicity in survivors, there remain gaps in our knowledge on screening, monitoring, prevention, and management of various cardiovascular toxicities. We remain in need of studies to understand real-world incidence and natural history of cardiotoxicity in the setting of newer targeted agents and changing treatment paradigms that shift treatment from a time-limited event to a more chronic setting. The optimal surveillance strategy will need to be further defined, including analyses of cost effectiveness and the outcomes of early medical intervention in asymptomatic survivors. Finally, further work in cancer survivors to define optimal interventions for risk factors (i.e., obesity, metabolic syndrome, and physical inactivity) and other CVD (such as arterial disease, arrhythmias, and valvular disease) are necessary. By focusing research efforts on knowledge gaps, guidelines can be refined based on solid evidence and expanded to incorporate the spectrum of cardiotoxicity rather than focus on a single problem.

In an attempt to address gaps in our knowledge, multiple professional societies have organized working groups or published scientific statements to identify needs and formulate research agendas for cardiovascular issues in cancer survivors, as well as to integrate the evaluation of cardiotoxicity into clinical trials with uniform definitions and phenotyping tools. The multidisciplinary Eastern Cooperative Oncology Group and American College of Radiology Imaging Network Cardiotoxicity Working Group was established to improve the understanding of cancer therapy-related cardiotoxicity mechanisms and to standardize the measurement and reporting of these events. This group has developed cardiovascular phenotyping tools, such as a cardiotoxicity case report form/data repository and a repository of biomarkers, imaging measures, and functional measures. The National Heart, Lung, and Blood Institute and National Cancer Institute co-sponsored an initiative to address gaps and formulate research recommendations for the hematopoietic stem cell transplant survivor population. Their Cardiovascular Disease and Associated Risk Factors Working Group recommended focused research in the following areas: arterial disease (coronary artery, cerebrovascular, and peripheral artery), cardiac dysfunction (HF, valvular, and arrhythmia), and cardiovascular risk factors (hypertension, hyperglycemia, hyperlipidemia, and sarcopenic obesity).24 The American Heart Association recently published a scientific statement on CVD and breast cancer, exploring the impact of shared risk factors and cancer therapies on outcomes and evaluating the current state of the science with an evaluation of gaps in current care and potential future directions for research to improve outcomes.25

Conclusions

Management of cancer can no longer be limited solely to the active treatment of malignancy. With increasing numbers of cancer survivors living longer, oncologists and other health care providers are faced with challenges in managing long-term and late toxicities of therapy, recognizing that cardiovascular issues are significant causes of morbidity and mortality in this population. The development of cardiotoxicity-focused guidelines represents early strides in improving overall patient-focused care. However, we must invest in additional research and foster multidisciplinary collaboration to tackle gaps in our knowledge and ultimately improve both cancer- and cardiovascular-related health outcomes in this growing population.

References

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Clinical Topics: Arrhythmias and Clinical EP, Cardio-Oncology, Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Noninvasive Imaging, Prevention, Valvular Heart Disease, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Lipid Metabolism, Novel Agents, Statins, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Echocardiography/Ultrasound, Magnetic Resonance Imaging, Exercise, Hypertension, Smoking

Keywords: Cardiotoxicity, Cardiotoxins, Aging, Algorithms, American Heart Association, Anemia, Angiotensin-Converting Enzyme Inhibitors, Anthracyclines, Antibiotics, Antineoplastic, Antibodies, Monoclonal, Humanized, Arrhythmias, Cardiac, Biological Markers, Blood Pressure, Body Weight, Breast Neoplasms, Carbazoles, Cardiomyopathies, Cardiovascular Diseases, Cause of Death, Colorectal Neoplasms, Comorbidity, Coronary Artery Disease, Coronary Vessels, Cost-Benefit Analysis, Dexrazoxane, Diabetes Mellitus, Disease-Free Survival, Doxorubicin, Dyslipidemias, Early Medical Intervention, Echocardiography, Epirubicin, Exercise, Habits, Health Behavior, Heart Failure, Heart Valve Diseases, Hematopoietic Stem Cell Transplantation, Hyperglycemia, Hyperlipidemias, Hypertension, Life Style, Lipids, Longitudinal Studies, Lung Neoplasms, Lymphoma, Non-Hodgkin, Magnetic Resonance Imaging, Maytansine, Medical Oncology, Melanoma, Metabolic Syndrome X, Multiple Myeloma, Muscle, Skeletal, Myocardial Infarction, Myocytes, Cardiac, National Cancer Institute (U.S.), Natriuretic Peptide, Brain, Obesity, Patient-Centered Care, Peptidyl-Dipeptidase A, Propanolamines, Quality of Life, Quinazolines, Reference Values, Referral and Consultation, Risk Assessment, Risk Factors, Risk Reduction Behavior, Smoking, Stroke Volume, Survivors, Survival Rate, Tobacco Use, Troponin I, Vascular Stiffness, Ventricular Dysfunction, Left


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